MOLECULAR GENETIC STUDIES OF SEROTONIN FUNCTION

对具有5 -羟色胺功能遗传缺陷的个体和动物的研究可以揭示这种神经递质在行为中的作用，以及5 -羟色胺基因中较轻的功能变异在使个体易患精神疾病和酗酒中的作用。我们正在通过测量脑脊液中血清素代谢物5-HIAA以及通过识别与血清素功能相关的基因中氨基酸替换的个体来确定家族研究的先证者。两个5-HT1A变体是罕见的氨基酸取代（Gly22Ser和Val28Ile），一个保守和一个非保守。5-HT2C变异是一种常见的（等位基因频率=0.18）非保守替代（Cys23Ser）。两个5HT2A氨基酸替换（Ala477Val和His452Tyr）的等位基因频率分别为0.01和0.09。还发现了罕见的5-羟色胺转运体和5-HT7氨基酸取代。其中三种氨基酸取代被证明改变了相应受体的功能特性。5HT1A Gly22Ser在CHO-K1细胞中表达时显著改变了这些受体的脱敏和下调。卵母细胞和COS-7细胞中的5HT2C Cys23Ser降低了配体结合5HT2A His452Tyr的水平，452Tyr等位基因受试者的血小板信号转导受损。为了进行关联和直接基因分析，我们从以下人群中收集了40多个细胞系：神经性厌食症（与W. Kaye合作），强迫症（D. Murphy），伴有II型酒精中毒的低CSF 5-HIAA （M. Linnoila， M. Virkkunen， M. Eggert）和季节性情感障碍（N. Rosenthal， N. Ozaki）。检测到的多态性被转化为PCR RFLPs或等位基因特异性扩增标记，以便于分析。利用CEPH参考谱系和这些基因的多态性，每个基因被遗传映射到其染色体位置。对于直接基因分析，我们主要使用单链构象多态性分析和直接测序。TPH多态性与冲动性酗酒芬兰人自杀倾向的关联被证实。在芬兰人（J. Lappalainen）中发现了5HT1B与反社会酗酒的兄弟对连锁，并在西南美洲印第安人中得到了重复。在一项兄弟对分析中，先前与神经质有关的血清素转运启动子变异5-HTTLPR与TPQ的两个焦虑相关亚量表有关（C. Mazzanti），部分重复了早期的发现。在一系列出版物中，我们已经证明5ht2a - 1438g bbbba启动子变体与焦虑相关疾病有关。这些包括强迫症、季节性情感障碍、神经性厌食症和来自三维人格问卷的焦虑相关量表。-人口研究，神经科学，基因定位（人类），分子遗传学，饮酒模式和原因

Studies on individuals and animals with genetic defects in serotonin function can shed light on the role of this neurotransmitter in behavior and on the role of milder functional variants in serotonin genes in predisposing individuals to psychopathologies and to alcoholism. We are identifying probands for family studies by measuring the serotonin metabolite 5-HIAA in cerebrospinal fluid and by identifying individuals with amino acid substitutions in genes involved with serotonin function. Two 5-HT1A variants are rare amino acid substitutions (Gly22Ser and Val28Ile), one conservative and one nonconservative. The 5-HT2C variant is a common (allele frequency=0.18) nonconservative substitution (Cys23Ser). Two 5HT2A amino acid substitutions (Ala477Val and His452Tyr) have allele frequencies of 0.01 and 0.09. Rare serotonin transporter and 5-HT7 amino acid substitutions were also discovered. Three of these amino acid substitutions were shown to alter the functional properties of the corresponding receptor. 5HT1A Gly22Ser when expressed in CHO-K1 cells dramatically altered desensitization and down regulation of these receptors. 5HT2C Cys23Ser in oocytes and COS-7 cells decreased ligand binding 5HT2A His452Tyr impaired signal transduction in platelets from subjects with the 452Tyr allele. For association and direct gene analysis, we have collected more than 40 cell lines from each of the following populations: anorexia nervosa (collaboratively with W. Kaye), obsessive compulsive disorder (D. Murphy), low CSF 5-HIAA with Type II alcoholism (M. Linnoila, M. Virkkunen, M. Eggert), and seasonal affective disorder (N. Rosenthal, N. Ozaki). The detected polymorphisms are converted to PCR RFLPs or allele-specific amplification markers for ease of analysis. Using the CEPH reference pedigrees and the polymorphisms at these genes, each gene is genetically mapped to its chromosomal location. For direct gene analysis, we mainly use single-strand conformational polymorphism analysis and direct sequencing. Association of a TPH polymorphism with suicidality in impulsive alcoholic Finns was replicated. Sib-pair linkage of 5HT1B to antisocial alcoholism was found in Finns (J. Lappalainen) and replicated in Southwestern American Indians. The serotonin transporter promoter variant 5-HTTLPR which was previously linked to neuroticism was linked to the two anxiety related subscales of the TPQ in a sib pair analysis (C. Mazzanti), partially replicating an earlier finding. In a series of publications, we have shown that the 5HT2A-1438 G>A promoter variant is linked to anxiety related conditions. These include OCD, seasonal affective disorder, anorexia nervosa and anxiety-related scales from the Tridimensional Personality Questionnaire. - population research, neurosciences, gene mapping (human), molecular genetics, drinking patterns & causes